The broad objective of this proposal is to define the role of the maternal, fetal and neonatal liver in the postnatal regulation of fuel metabolism and nutrient assimilation by infants of diabetic mothers (IDM). A previously used canine model of non-ketotic diabetes mellitus during pregnancy will be employed to examine hypotheses inferred from human investigation with stable isotopic tracers and low-rate glucose infusions. Specifically, glucose:amino acid and glucose:fat interrelations will be examined under conditions of fasting and of exogenous substrate provision. Glucose turnover, gluconeogenesis, hepatic ureagenesis and diversion of glucose metabolism will be examined simultaneously in the pregnant dogs and newborn puppies with multiple radioisotopic and stable isotopic tracers. Systemic isotope dilution and product enrichment in vivo will be quantified by Beta-scintillation and mass spectrometry. Intrahepatic regulation will be defined by assaying enzymatic activities and by characterizing allosteric regulation at rate-controlling sites in vivo. In order to perform such studies in the framework of an appropriate experimental design, hypotheses were generated concerning the regulation of substrates and fuels by nutrient ingestion or by fasting. In the newborn offspring of a diabetic mother, 6 arbitrarily defined fetal and neonatal "states" were linked by a hypothesis integrating hormonal control, enzymatic activation, and allosteric regulation. This approach describes the altered sequence of adaptation occurring in the IDM, and develops safe methods for human investigation. Finally, pilot studies of hormonal modulation and allosteric regulation of neonatal glucose metabolism are described in newborn infants. These studies will utilize methods which have been applied safely in investigatons of mammals, adult man, and newborn infants.